The multiple physiological, pathological and immunological effects of bacterial lipopolysaccharides (LPS, endotoxins) are well-documented. Nevertheless, the precise nature of the interaction of LPS with humoral and cellular mediation systems resulting in disseminated intravascular coagulation (DIC) with subsequent tissue damage or modulation of the immune response remains unclear. This has, in part, been the result of a lack of recognition that the LPS from different bacteria may differentially affect the various mediation pathways. Our objective is to first define the biophysical and biochemical parameters of the LPS molecule which are responsible for its diverse biological activities in vitro and then to delineate the participation of these activities in LPS-initiated host responses in vivo. Although all preparations of LPS share structural and chemical similarities we have shown that minor differences profoundly affect LPS biological activity. In addition, we can modify the LPS structure and/or composition to differentially affect its biological activities. Selected naturally occurring or chemically modified preparations of LPS will be examined in vitro for their ability to interact with humoral mediation systems, (classic and alternate complement pathways and the Hageman factor related-kinin forming, intrinsic clotting and fibrinolytic) systems and cellular mediation systems (platelets, mast cells, neutrophils, and macrophages). LPS-induced DNA synthesis (mitogenesis) in B-lymphocytes and stimulation of a polyclonal (T cell independent) immune response will also be examined. Preparation of LPS which have been demonstrated to differentially affect the various mediation systems will be examined for their capacity to initiate physiological and hematologic changes (including hypotension, temperature, peripheral blood cell counts, and plasma protein concentrations). We will, in addition, examine pathological changes with primary emphasis on the deposition of fibrin (DIC). Finally, the capacity of altered preparation to modulate the immune response (immunogenicity and adjuvanticity) will be examined. A correlation of the in vivo and in vitro activities of LPS preparations with differential activities should contribute significantly toward an understanding of the mechanism(s) of LPS-initiated host responses.